12th Congress of the European Hematology ... - Haematologica

0029
OUTCOME OF THE TREATMENT OF ADULT ACUTE LYMPHOBLASTIC LEUKEMIA USING A
PEDRIATRIC PROTOCOL
S. Haiat, A. Vekhoff, C. Marzac, O.A. Calendini, S. Lapusan,
Z. Marjanovic, B. Rio, J.P. Marie, O. Legrand
Hopital Hotel Dieu, PARIS CEDEX 04, France
Background. Adult acute lymphoblastic leukemia (ALL) still have poor
outcome compared with childhood ALL, with an expected long time
survival of less than 40%. Adolescents aged from 15 to 20 years have
improved complete remission (CR) and event free survival (EFS) rates
when treated with pediatric protocol instead of adult one. Aims. In a
pilot study, we have tested the feasibility and the efficiency of the French
pediatric protocol FRALLE 2000 to treat adult ALL aged up to 55 years.
Methods. 20 consecutive adults Philadelphia negative ALL aged from 15
to 55 years received treatment courses according to the French pediatric
protocol FRALLE 2000 from 2001 to 2006. After a prednisone prephase
and a four-drugs induction (prednisone, daunorubicin, vincristine and 9
infusions of L-asparaginase), patients in CR received a consolidation
course, two delayed intensifications with L-asparaginase separed by an
interphase, a CNS irradiation and a maintenance chemotherapy during
two years. Results were compared with the outcome from 20 consecutive
patients treated in our institution with the historic EORTC ALL-4
adults protocol from 1998 to 2001. Median age, WHO performans status,
white blood count at diagnosis, phenotype and cytotogenetics risk
groups were statistically similar in both groups. Results. Cortico-sensitivity
and chemo-sensitivity was assessed for 15 and 17 patients respectively
and CR rate was 85% after FRALLE induction, and 100% after a salvage
therapy with high doses cytarabine. All patients who achieved cortico
and chemo-sensitivity were in persistant CR with a median followup
of 26 months. Minimal residual disease (MRD) study was available
for 12 patients, using IgH/TCR rearrangement or E2A/PBX1 transcript.
Among the 10 patients with an indetectable MRD at D90, no one experienced
relapse. Overall, with a median follow-up of alive patients of 26
months, the 4-years EFS and overall survival are 80±10% vs 47±12%,
(p=0.04) and 87±9% vs 35±16%, (p=0.03) respectively. This better outcome
is not explained by significant differences in patients characteristics
nor by a better CR rate but rather by a lower relapse rate in the pediatric
treatment group (more than two-fold lower). This indicates a major
role of the drugs indication and the dose intensity, especially in Lasparaginase
administration. No treatment related mortality and no
severe side effect were observed during treatment with supportive cares
including parenteral nutrition, granular growth factor, infectious prophylaxis,
and antithrombine III infusions. Summary and conclusions. This
pilot study shows that adults up to 55 years with Ph negative-ALL have
a dramatically better outcome when there are treated with childhood
ALL protocol without any major side effect. This therapeutic strategy has
to be confirmed by the current prospective study performed by the
EORTC group.
12 th Congress of the European Hematology Association
Acute myeloid leukemia - Biology I
0030
EXPRESSION OF ANGIOPOIETINS AND VASCULAR ENDOTHELIAL GROWTH FACTORS AND
ITS CLINICAL SIGNIFICANCE IN ACUTE MYELOID LEUKEMIA: ANG-2 EXPRESSION IS AN
INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL
H.-A. Hou, W.-C. Chou, L.-I. Lin, J.-L. Tang, M.-H. Tseng, C.-F. Huang,
M. Yao, C.-L. Chen, S.-Y. Huang, C.-Y. Chen, B.-S. Ko, W. Tsay,
Y.-C. Chen, H.-F. Tien
National Taiwan University Hospital, TAIPEI, Taiwan
Background and Aims. Concerted expression of angiopoietins, their
receptor Tie2 and vascular endothelial growth factor (VEGF) family, most
specific inducers of angiogenesis secreted by leukemia blasts, are known
to play an essential role in normal and pathologic angiogenesis. We therefore
evaluate the clinical implication of angiogenic factors in patients
with acute myeloid leukemia (AML). Methods and Patients. We investigated
the RNA expression of genes encoding angiopoietin-1 (Ang-1),
angiopoietin-2 (Ang-2), the receptor Tie2, VEGF-A and VEGF-C by realtime
quantitative polymerase chain reaction (RQ-PCR) in a cohort of
126 patients with newly diagnosed de novo AML at National Taiwan
University from June 1995 to Feb 2006. The results were correlated with
clinical features and outcome of the patients. Results. Expression of Ang-
1, Ang-2 and VEGF-A was significantly higher and that of VEGF-C was
lower in AML patients than in normal controls. RNA expression level
correlated well with the results of immunocytochemical staining in the
selected patients studied. Patients with high Ang-1, Ang-2, or Tie2
expression had significantly shorter relapse-free survival than those with
low expression (8 months versus 14 months, p=0.029; 9 months versus
14 months, p=0.01; 8.5 months versus 14 months, p=0.01, respectively)
by univariate analysis, but the significance disappeared by multivariate
analysis. On the other hand, high expression of Ang-2 and Tie2, but not
other angiogenic factors, was correlated with a shorter overall survival
(15.7 months versus 38 months, p=0.005; 14 months versus 26 months,
p=0.043, respectively). In multivariate analysis, only karyotype and Ang-
2 expression were independent prognostic factors, with a hazard ratio
of 2.19 (95%CI, 1.27-3.77, p=0.005) and 2.05 (95%CI, 1.20-3.52,
p=0.009), respectively. Furthermore, the prognostic relevance of Ang-2
expression became even more pronounced in the patients with intermediate-risk
karyotype (p=0.004). Subgroup analysis showed that the prognostic
impact of Ang-2 expression was only evident in the patients with
low Ang-1 or low Tie2 levels, but not those with high levels, and in the
patients high VEGF-A or high VEGF-C levels, but not those with low levels.
Conclusions. These results provide evidence that high pre-treated levels
of Ang-2 in the bone marrow indicate an unfavorable prognosis in
AML. Further research into interaction of concerted angiogenic factors
in AML is warranted.
0031
MUTATED NUCLEOPHOSMIN (NPM1) IS ASSOCIATED WITH INCREASED SPONTANEOUS
APOPTOSIS AND FAVORABLE PROGNOSIS IN FLT3-ITD NEGATIVE ACUTE MYELOID
LEUKEMIA (AML)
G. Del Poeta, E. Ammatuna, S. Zaza, F. Buccisano, T. Ottone, M.I. Del
Principe, S. Lavorgna, G. Catalano, F. Luciano, L. Maurillo, L. Ottaviani,
A. Bruno, A. Venditti, P. De Fabritiis, S. Amadori, F. Lo-Coco
University Tor Vergata, ROME, Italy
Nucleophosmin (NPM1) is a multifunctional protein that interacts
with p53 and its regulatory molecules (ARF, Hdm2/Mdm2), thus controlling
cell proliferation and apoptosis (Falini et al, 2007). Mutations in
NPM1 occur in up to 50% to 60% of normal karyotype acute myeloid
leukemia (AML) patients and are associated with more favorable
response to therapy. Moreover, genes and proteins involved in apoptosis
have been shown to be relevant in response to treatment and prognosis
in AML (Del Poeta et al., 2003). We analysed NPM1 mutational status
and the expression of apoptosis proteins (bcl-2 and bax) in 188 pts
affected by de novo non-M3 AML. Median age was 61 yrs (range 21-82)
and patients received treatment according to the GIMEMA-EORTC
cooperative groups protocols. The aims of our study were: 1) to correlate
the NPM1 status with bax/bcl-2 ratio levels, as a measure of spontaneous
apoptosis, and 2) to assess the prognostic significance of NPM1
and FLT3 status in relation to the bax/bcl-2 ratio. Bcl-2 and bax proteins
were determined by multicolor flow cytometry and bax/bcl-2 ratio was
obtained by dividing mean fluorescence intensity (MFI) of bax/MFI bcl-
2. The threshold of positivity was set at the median value >0.3. NPM1
haematologica/the hematology journal | 2007; 92(s1) | 11